Nuclear receptors are classically defined as a family of ligand dependent transcription factors that are activated in response to ligand binding. Members of this family include the following receptors: glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally occurring ligands to these receptors are low molecular weight molecules that play an important role in health and in many diseases. Excesses or deficiencies of these ligands can have profound physiological consequences. By way of example, glucocorticoid excess results in Cushing's Syndrome, while glucocorticoid insufficiency results in Addison's Disease.
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by the binding of a ligand. Upon stimulation, the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and either activates or represses transcription in a glucocorticoid responsive manner. Activation involves glucocorticoid receptor binding to specific DNA sequences (glucocorticoid response elements or GREs) and the association with other factors, including coactivators that were discovered on the basis of their ability to increase the total levels of induced gene product. Repression usually involves glucocorticoid receptor becoming tethered to proteins bound to non-GRE DNA sequences as opposed to the direct binding of glucocorticoid receptors to DNA sequences. Two examples of DNA-bound proteins that interact with glucocorticoid receptors, and participate in glucocorticoid receptor-mediated gene repression, are AP-1 and NFκ-B. These interactions of glucocorticoid receptor are believed to be responsible for some of the anti-inflammatory activity of exogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription.
Three distinguishing properties of ligand-regulated gene induction by glucocorticoid receptors are 1) the level of activated gene expression with agonist steroids, 2) the concentration of agonist required for half-maximal induction (EC50), and 3) the amount of partial agonist activity with antagonists or antisteroids. The last two properties are independent of the total amount of gene expression, and basal level activity, due to the mathematical method by which they are defined. Physiological concentrations of steroid are often similar to the EC50 of inducible genes. Therefore, those regulated genes that have lower EC50s, and dose-response curves that are more left-shifted, will be preferentially induced by the circulating hormone, thereby affording differential gene induction during development, differentiation, and homeostasis. Endocrine therapies using antisteroids will be much more specific if one can increase the partial agonist activity for most genes and limit the repression to one or a few regulated genes.
Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from eliciting GR mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
However, while glucocorticoid receptor agonists can be beneficial agents for the treatment or prevention of various diseases and conditions, such treatment is often accompanied by undesirable side effects. These side effects include, for example, metabolic effects, weight gain, muscle wasting, decalcification of the skeleton, osteoporosis, thinning of the skin and thinning of the skeleton. Hence, agents are needed that modulate glucocorticoid receptor activity without causing these types of side effects. Moreover, glucocorticoid antagonists and agonists that act selectively may be desirable in therapies for the selective blockage/enhancement of specific genes without simultaneously influencing other glucocorticoid-responsive genes.